Sustained action pill



March 15, 1960 F. M. BARDANl SUSTAINED ACTION PILL Filed Nov. 28, 1958INVENTOR. FRANK Mv BARDANI WW,ALHM

ATTOF/VEVJ' United States Patent l SUSTAINED ACTION PILL Frank M.Bardani, Plainview, N.Y. Application November 28, 1958, Serial No.777,131

8 Claims. (Cl. 167-82) This invention relates to pills which sustainmedication of the alimentary canal over extended periods of time.

Medication for the purposes of combating diseases, acting on the nervoussystem or affecting the body in any manner may be accomplished orally orby injection. The oral method is preferred in most instances because itenables self-medication of the patient.

Oral medication may take the form of powders, tablets, capsules, pillsand the like. Because of the strong taste of many medicaments and thenecessity for releasing them within selected portions of the alimentarycanal; i.e., the stomach and intestines, pills are favored formedication in many circumstances. Generally pills have been formed byprotecting a medicament with a desired coating to facilitate ingestionand passage into the alimentary canal. The coating used was chosen toeffect medication of a desired portion of the alimentary canal. Whenmedication of the stomach was desired, the coating was formulated toresist fluids encountered in the mouth and during passage into thestomach. The gastric fluids there encountered disintegrated the coatingand rapid dissolution of the medicament followed.

When it was necessary to release medicament in the intestines, so-calledenteric coatings unafiected by stomach fluids were used to ensurepassage of such medicament through the stomach to the intestines. Suchenteric coatings when immersed in intestinal fluids were attacked anddisintegrated or destroyed and the medicament quickly released. I

Sudden release or dumping of large quantities of medicament into thealimentary canal is most undesirable. First, the body cannot absorblarge quantities of medicament in a short interval and much will bewasted. Second, and of greater concern, release of too great a quantityof medicament can place the patient in a condition of shock, and causeinjurious side effects.

Attempts to provide sustained medication in the gastrointestinal tracthave included the use of great numbers or individual granules or pilletscoated to release medicament at varying times. Difiiculties have beenencountered because of the necessity of timing the granules to releaseover a long period. If an excessive num er of granules releasedmedicament simultaneously rather than sequentially, overdo-sage resultedrather than a sustained therapeutic effect.

Pills have also been used first to release medicament in the stomach andthen, after being passed to the intestines, to provide medicationtherein. The time a pill remains in the stomach varies greatly and maybe from under one-half hour to two or more hours. If a pill is designedto release medicament into the stomach a few minutes after ingestionwith the assumption that it will be passed along in an hour to theintestines to release further-medicament, and the pill is thereuponpassed within one-half hour to the intestines, the patient may besubjected to a double dose with injurious results. On the other hand, ifthe pill is retained in the stomach 2,928,770 Patented Mar. 1 5, 1960for two hours and then passed to the intestines, the time intervalbetween release in the stomach and in. the intestines may be so great asto provide an interval without medication.

In an attempt to remedy this situation, pills have been designed torelease medicament in the stomach about one-half hour after ingestion.If such pills are passed into the intestines before release of thestomach dose, a double dosage of medicament is released directly to theintestines with possible bad efiects on the patient. 7

The present invention provides pills which release medicament in thealimentary canal over a wide range of desired periods to sustainmedication for long intervals. Such release enables the body to absorband use far greater percentages of the medicament than if single largerdoses were administered, thereby greatly increasing the etliciency ofmedication. Moreover, sustained medication of the alimentary canaleliminates injurious side effects resulting from the dumping of largequantities of medicament into the system. The impact of the drug is notmade on the body during a relatively short interval, as in the past, butis distributed over the period of its release, thereby facilitating useof the drug by the system.

Sustained medication pills in accordance with the principles of thepresent invention are formed of layers of medicament separated bycontrol coatings. Each coating includes a porous membrane, initiallyhaving a substance closing its pores, to control the flow of alimentaryfluids therethrough to the medicament. The time each coatin withstandsthe fluids before becoming porous and the rate of flow of fluids throughthe coating is determined by its composition and the manner in which itis formed on the medicament layers. Moreover, the time over whichmedication must be sustained determines the number of layers ofmedicament and the number of control coatings or membranes interposedbetween such layers.

Upon subjection of the sustained action pill to alimentary fluids, thematerial closing the pores is gradually removed and fluids flowingthrough the resultant permeable membrane leach medicament therethrough.Before complete dissolution of one medicament layer, the next coating iswetted by the fluids to initiate opening of its pores. During therelease of medicament, the control coating or membrane remains intactuntil at least the medicament thereunder is dissolved and passed intothe alimentary canal.

One form of sustained action pill according to the invention providesmedication in both the stomach and intestines. The coating used in thestomach is of a different composition from that used in the intestines,due 'to the acidity of the stomach and alkalinity of the intestines.This pill medicates the stomach while it remains therein. Passage of thepill to the intestines results in dissolution of the stomach coating orcoatings by the intestinal fluids which then initiate leaching of theremaining layers of medicament through the intestinal control coatingsinto the intestines. The first medicament released may stimulate thestomach to empty into the intestines, and such pill may then act as as alaxative in the intestines. The pill bars exposure of the two differentdrugs to each other which precludes 7 a number of the inventive pillsinto a capsule, larger pill or tablet. A patient may then ingest aselected number of sustained action pills in convenient form, the smallpills or pillets medicating the gastro-intestinal tract over an extendedperiod.

These and further objects and advantages of the present invention willbe more readily understood when the following description is read inconnection with the accompanying drawings, in which:

Figure l is an elevation, partially broken away, of a pill formed inaccordance with the present invention;

Figure 2 is a view in perspective, partially broken away,

of a tablet containing a plurality of the pills of Figure 1; Figure 3 isan elevation of a larger pill, partially broken away, containing aplurality of the pills of Figure' 1; and ,.:.";Figure'4'is an elevationof a capsule, partially broken away, co'ntaining'a plurality ofsustained action pills. Referring to an illustrative embodiment of theinvention with referenceto Figure l, a pill -is formed of aplurality oflayers of medicament separated by control coatings. An outer layer ofmedicament 11 for medica- [tion of the alimentary tract surrounds thepill 10. A sugar coating or thin polished wax layer may be placed overthe layer 11, if desired, in accordance with conventional practice inthe pill manufacturing art.

The term medicament used herein refers to any substance that it may bedesirable to release for medication in the gastro-intestinal tract forany purpose. For example, pills formed in accordance with the inventionmay include antibiotics such as the following: penicillin, Tetracycline,Terramycin, Aureomycin and Chloromycetin; sedatives and hypnotics, asfollows: pentabarbital sodium, phenobarbital, secobarbital sodium,codeine, Bromisovalum, carbromal and sodium phenobarbital; hypotensivesand vasodilators, as follows; pentaerythritol, erythrityl tetranitrateand nitroglycerin; amines as follows: dl amphetamine sulfate anddextroamphetamine sulfate; hormones as follows; Dienestrol, Diethyl,stilbestrol, Methyltestosterone and Progesterone; cortisone; vitamins;and tranquilizers as follows; reserpine, chlorpromazine hydrochlorideand thiopropazate hydrochloride. 4 Immediately beneath the layer 11 is acoating or control membrane 12 to control the flow of alimentary fluidsto a medicament layer 13. The coating 12 consists of a thin compositemembrane including pores initially closed by a suitable substance.Alimentary fluids act on the coating to remove after a period of timesufficient amounts of the closure substance from the pores to render thecoating permeable. The resulting permeable membrane controls the flow ofalimentary fluids to the medicament layer 13. Such fluids dissolve themedicament and leach it out of the pill 10 through the permeablemembrane.

The coating 12 must be tough enough to withstand agitation and abrasionin the alimentary canal without rupturing which would permit suddenrelease of the medicament layer 13. Instead of sudden release by thepill 10 of all of its active ingredients into the alimentary tractwithin a minute or two after exposure to alimentary fluids in the mannerof ordinary pills, which use protective coatings that disintegrate orrupture before or during release of the medicament, the control coating12 remains intact after its pores have been opened to control release ofmedicament from the single layer 13.

Before the layer 13 is wholly leached through the permeable membrane,formed from the coating 12, into the gastro-intestinal tract, thealimentary fluids wet a further coating 14 and initiate removal of itspore sealing substance to render it permeable. Fluids passing throughthe coatings 12 and 13 then leach medicament out of a further layer 15.Inthis manner medication of the gastro-intestinal tract by the pill 16may be suatt il ed over any desired period limited only by the length oftime the body retains the pill.

Extensive use has been made of membranes that provide controlled releaseof medicament .in the alimentary canal for about one hour. For example,the membrane withstands fluids for about 45 minutes before becomingpermeable and then provides release of medicament for about 15 minutes.Accordingly, if six layers of medicaments are separated by one hourcontrol coatings, such pill will provide effective medication of thealimentary canal for about 6 hours. As pointed out hereinafter, bysuitably varying'the composition and thickness of the coatingsand themanner of forming such coatings, release of medicament may be controlledby each coating for greater or lesser periods.

Assuming the use of control coatings or membranes in the pill of Figure1 that each provide medication for one hour, subsequent to dissolutionof the outer layer 11 .of the. pill 10 the five coatings will providerelease ofthe five medicament layers during a 5 hour period.

Formation of the permeable membrane after the alimentary fluids wetthecoating appears to follow a swelling action of the film or membranematerial together with a softening, weakening and at least partialdissolution of the pore closure substance. Such swelling seems to breakthe softened closure substance out of the membrane pores. Bodytemperatures apparently assist this action. The coating 12, afterexposure to alimentary fluids, has the physical characteristics of avery fine mesh screen which passes alimentary fluids in con-trolledfashion to the medicament. Moreover, the coating 12 re mains intact andfunctions to control the passage of alimentary fluids at'leastuntil itscorresponding medicament layer is released to the alimentary tract.Sudden release of medicament and overdosage is thereby avoided.

Tests have shown that medication is much more efficient and effectivewhen applied over an extended period. The body absorbs a far greaterpercentage of medicament released in this manner than if the same amountof medicament found in the several layers of the pill were dumpedsuddenly into the alimentary canal. Moreover, dumping or sudden releaseof medicament can shock the system and res ult in serious side effects.

If medication of the stomach and intestines is required, the pill 10 ofFigure 1 may be formed of medicament and coatings for use in the acidfluids of the stomach and the alkaline fluids of the intestines. Themedicament layer 11 will be released immediately to the stomach or, ifomitted, as is often the case, gastric juices wetting the coating 12will open its pores and the resultant permeable membrane will controlfluid flow to the medicament layer 13. For example, the coating 12 maycomprise a porous film of cellulose acetate phthalate (obtainable fromEastman Kodak Co. in powder form and mixed andcoated as set forthhereinafter) together with beeswaxblocking its pores.

To form an exemplary coating 12, a solution may be prepared fromcellulose acetate phthalate and beeswax in a vehicle of acetone in suchproportions that a thin coating on the medicament will, after immersionin stomach fluids, form a permeable membrane controlling the'flow' offluids therethrough. The medicament 13 beneath the permeable membrane issubsequently leached through the membraneinto the stomach while themembrane remains intact.

For example, a film comprising from to by weight of cellulose acetatephthalate and from 5% to 20% by weight of beeswax has been found toprovide a satisfactory membrane 12. Such coating may be pre pared bydissolving those components in a solvent such as acetone. The solutionmay also contain, in place of beeswax, carnuba wax, for example from 10to 30%. The cellulose acetate phthalate-wax solution is then coated onthe medicament layer 13 as described in detail e einafter to form a coatng controlling the release or medicament. The coating 12- is very thinhaving the approximate thickness of thin onionskin paper.

An exemplary cellulose acetate phthalate solution com prises 300 gramsof cellulose acetate phthalate and 30 grams of beeswax dissolved in 1500cc. of acetone, the resulting solution being disposed on the medicamentlayer 11 by conventional coating methods to form the control coating 12.The solids concentration of the coating solution may be varied todetermine, to some extent, the thickness of the coating 12. Moreover,the number of times the solution is coated on the pills also determinesthe coating thickness. In turn, the coating thickness is one factordetermining the timing of release of medicament by the stomach fluids.The thicker the coating, the longer it will withstand the stomach fluidsbefore becoming permeable and releasing medicament in a controlledmanner to the stomach. Such release also depends on the composition ofthe coating, the solubility of the medicament and the manner of applyingand heat treating the coating.

In use, the pill is ingested into the stomach and the outer medicamentlayer 11 dissolves rapidly in four or five minutes. The outer layer 11may be omitted if the pill must reach deep within the stomach beforerelease of medicament. Exposure of the coating 12 to gastric juicecauses swelling of the cellulose acetate phthalate film and the softenedwax is accordingly broken out of its pores. Stomach fluids pass throughthe permeable membrane, dissolve the medicament 13 and leach it out ofthe pill 10 for medication of the stomach. V

In controlling release of the medicament layer 13, the coating 12impedes the flow of stomach fluids and maintains medicament release fora longer interval than if the layer 13 were exposed directly to stomachfluids. For example, medicament may be released from the pill for aminute period following a minute period of exposure to stomach fluids.In addition, the coating 12 is tough enough to withstand agitation andabrasion in the stomach.

It has been found that, other factors being equal, if the percentage ofbeeswax in the coating solution is increased, the period that thecontrol coatings withstand exposure to stomach fluids before becomingpermeable is decreased while a decrease of the amount of wax in thecoating solution results in the opposite effect.

Preferably, the control coating 12 and any further coatings that may beused to release medicament in the stomach are formed of materials thatwill dissolve in the alkaline intestinal tract when the pill proceeds tothe intestines from the acid stomach. Upon entry into the intestines, asecond type of control coating or membrane 14 is exposed to the fluidstherein, such coating also forming a permeable membrane to control theflow of intestinal fluids therethrough to provide medication in theintestines. H

A n exemplary coating 14 is formed of ethyl cellulose and shellac insuch proportions that a thin coating becomes permeable by intestinalfluids. A coating comprising about 70% to 95% by weight of ethylcellulose and about 5% to 30% by weight of shellac, for example,provides satisfactory results. These percentages are varied inaccordance with the time the membrane must withstand the intestinalfluids, the coating thickness, the solubility of the medicamentand theheat treatment of the pills as described hereinafter. In some instancesthe percentages may fall outside of those specified which are not to betaken as critical. Such control coatings may be prepared by dissolvingthese components in a vehicle such as alcohol. The resulting ethylcellulose solution may then be coated by conventional methods on thepill 10 over a layer of medicament 15 intended for release in theintestines, the membrane being very thin as described in connection withthe coating 12. I As a specific example of an ethyl cellulose solution,

300 grams of ethyl cellulose and 30 grams of shellac may be dissolved in3000 cc. of alcohol and the resulting solution coated on a layer ofmedicament 15 such as potassium penicillin or tetracycline to form thecontrol coating 14, as described in detail hereinafter. I

. The coating 14 will be exposed to the stomach fluids after the layer13 has been dissolved, if the pill 10 has not yet passed to theintestines. However, the ethyl cellulose and shellac coating 14 isunaffected by such fluids so that the medicament layer 15 therebeneathwill be passed into the intestines without being affected in thestomach.

After being wetted by intestinal fluids, removal of the pore closingshellac of the control coating 14 is initiated and intestinal fluidsthen flow through the resulting permeable membrane to leach themedicament layer 15 into the intestines in a controlled manner.

The proportion of shellac in the coating 16 is one factor thatdetermines the rate at which medicament will be released from the layer15. The thickness of the coating 16 and heat treatment of the pill alsoare factors in such release. Thus, other factors being equal, a greaterpercentage of shellac decreases the periodlthat the coating willwithstand the intestinal fluids before becoming permeable while athicker control coating increases that period.

The coating 14 must also have characteristics enabling it to withstandconsiderable agitation and abrasion as it travels through the intestinaltract. Ethyl cellulose is admirably suited to perform this functionsince it affords a tough resilient skin on the pill 10 in theintestines.

Prior to complete dissolution of the medicament layer 15, intestinalfluids wet the next control coating 16, simi lar to the coating 14, andopening of its pores for penetration by the intestinal fluids to themedicament 17 therebelow is initiated. The time which the controlcoating 16 is designed to withstand the intestinal fluids beforebecoming permeable depends on the absorption characteristics of themedicament. If the drug in the pill 10 is absorbed quickly and then hasa therapeutic effect for one hour, for example nitroglycerin, thecoating 16 may be designed to initiate release of a medicament layer 17within one hour after the intestinal fluids wet the control coating.With such drugs a fairly large number of layers of active material, forexample ten layers, separated by control coatings may be used to sustainmedication over about a 10 hour period with proper heat treatment of thepills as described hereinafter.

On the other hand, if a drug absorbed slowly by the intestines maintainsits therapeutic effect for several hours, for example potassiumpenicillin, the control coating 16 may be designed to withstandintestinal fluids for several hours before becoming permeable tointestinal fluids. Thus, such a-coating would use less shellac, be

thicker, and heat treated in a manner to insure such function. Withdrugs having longer lasting therapeutic effects, it is apparent that alesser number of layers need be provided since the release of medicamentfrom one layer will provide medication for several hours. For example,it has been found that a pill incorporating two layers of potassiumpenicillin separated by a control coating designed to withstandintestinal fluids about seven hours provides medication in excess ofsixteen hours.

Returning to the pill 10 shown in Figure 1, medication of the intestinesprovided by the medicament layer 17 is then sustained due to the releaseof further quantities of medicament 19 and 21 through further controlcoatings 18 and 20 in timed sequence. If each coating providestherapeutic effects for about one hour, the pill 10 illustrated will beeffective for at least 6 hours. Any greater or lesser number ofmedicament layers and permeable coatings may be used so that theinventive pill may provide medication and therapeutic effects for anydesired period. In that regard, the length of time pills remain in theintestines ranges from a period of about 4 hours to a period in excessof 16' hours.

The coatings 14, 16, 18 and 20 become permeable membranes after exposureto intestinal fluids but remain intact throughout the period of releaseof the medicament layers therebeneath to control medication of theintestines. In contras known enteric coatings rupture or disintegrateafter exposure to intestinal fluids and, accordingly, medicament inrelatively large quantities is dumped into the intestinal tract at onetime.

A further exemplary coating that may be utilized to sustain medicamentrelease in the alimentary tract includes ethyl cellulose andpolyethylene glycol. For example, 100 grams of ethyl cellulose and 3grams of polyethylene glycol (Carbowax No. 6000 for example) may bedissolved in 1000 cc. of alcohol and the resulting solution coated in aconventional manner on a plurality of layers of chloroprornazine, forexample, in a pill to provide sustained medication in the intestinaltractas described above. Such coatings when heat treated as specifiedhereinafter and exposed to intestinal fluids initially inhibit for aperiod and then control the flow of intestinal fluids to the medicamentlayers therebeneath and in such manner sustained medication andtherapeutic efiects for desired periods.

Since pills remain in the intestines for much longer periods than in thestomach, release of drugs and medication may continue over longerperiods inthe intestines than in the stomach so that ordinarily, agreater number of medicament layers, separated by intestinal fluidcontrolling coatings, are used when medication over extended periods isdesired.

Tests of 180 patients have shown that the average time a pill remains inthe stomach is approximately 47 minutes. A single permeable membraneprovided by the invention has been found to withstand stomach fluids forany fraction of that period and then to become permeable and releasemedicament so that it is not necessary ordinarily to employ more thanone coating to release a single medicament to the stomach. However, inthe event two or more medicaments must be released sequentially in thestomach, two or more coatings each providing release for about 10minutes at 20 minute intervals, for example, may be coated over layersof medicament to provide such sequential release pills.

x The invention can be illustrated by the following examples:

EXAMPLE I Step 1.Mix 2.5 gm. of dextroamphetamine sulfate with 100 gm.of powdered sugar (dextrose). Moisten this mixture with =10 cc. of waterand thoroughly dry at a temperature at 80 F. To this mixture add 2.5 gm.of magnesium stearate (for lubrication to prevent sticking duringcompression) and compress into 1000 spherical cores or pillets eachweighing 105 mg. with a diameter of %2".

Step 2.Prepare a solution A, which will provide a coating resistant tostomach fluids and permeable after exposure by intestinal fluids, bymixing 5 gm. of ethyl cellulose, 1 gm. of shellac and 94 cc. of methylalcohol. Prepare a solution B, which provides a coating permeable afterexposure by stomach fluids, by mixing 5 gm. of cellulose acetatephthalate, 1 gm. beeswax and 94 cc.

acetone.

Step 3.-Rotate the pillets formed by step i in a coating pan whileadding 5 cc. of solution A. During such coating maintain the temperatureat the pill surfaces between 90 and 100 F. After allowing the pills todry for 15 minutes at room temperature, add another 5 cc. of solution Awhile rotating the pills in the coating pan at the same temperature.Each coating or membrane thus formed will withstand intestinal fluidsfor about 45 minutes and release a layer of dextroamphetamine sulfateover a period of about 15. minutes, depending on the final heattreatment, as stated in step 7.

Step 4.Dissolve 2.5 gm. of dextroamphetamine sulfate and 22.5 gm. ofpowdered sugar (dextrose) in 200 cc. of water and cc. of methyl alcohol,mix well and apply to the pills in a coating pan to provide a medicamentlayer about 4 thick. Allow the pills to dry for a period of about thirtyminutes. Each pill will now weigh mg.

Step 5.Repeat steps 3 and 4 a total of three times. Each pill will nowweigh mg.

Step 6.-While rotating the pills in a coating pan add 5 cc. of solutionB while maintaining the temperature at the pill surfaces between 90 and100 F., allow to dry andvthen add another 5 cc. of solution B. Thecoat-, ing or membrane thus formed will withstand stomach fluids forabout 45 minutes and then release through it's opened pores thedextroamphetamine sulfate for about '15 minutes depending on the'flfinalheat. treatment. Dissolve 2.5 gm. of dextroamphetaminesulfate and 22.5gm. of powdered sugar (dextrose) in 200 cc. of water and 100 cc. ofmethyl alcohol, mix well and apply about a ,4 layer to the pills in acoating pan. Each pill will now weigh 205 mg.

Step 7.-Place the pills in an oven maintained at 97 to 98 for heattreatment for a period of 4 hours.

S'rep 8.-Coat the pills with 1 pint U.S.P. syrup containing 100 mg. redcolor until a weight of 299.5 mg. is reached. Then polish the pills witha solution of .25 gm. of beeswax, .25 gm. of carnuba wax in 10 cc. ofacetone. Each pill will now Weigh 300 mg.

The pills formed in accordance with Example I will provide continuoustherapeutic effects for about 6 to 7 hours due to release of medicamentin the stomach over about a 2 hour period and in the intestines overabout a 4 to 5 hour period. In other words, although there are only 4layers of medicament (including the center pillet) released in theintestines, the sequence of release in the intestines is such that itwill beabout 4 hours (6 hours if the stomach period is included) beforsubstantially all of the material isreleased. Of course, absorption andtherapeutic effects continue for some time after the release of the drugis completed.

If a slower release of medicament is desired, the pills may be heattreated for 6 or 8 hours and medication will be sustained in the.alimentary tract 8 to 9 or 9 to 10 hours, respectively. Thus, a factorin the time that the control coatings withstand alimentary fiuids is theperiod during which the pills are heat treated.

The heat treatment dries the pills and causes the pore closure substanceto enter and close the pores in the permeable membrane. The longer theheat treatment, the greater the drying and entry of shellac, forexample,

into the pores of the ethyl cellulose, and the longer the controlmembrane will Withstand alimentary fluids before being renderedpermeable. I

The duration of heat treatment must also be related to the solubility ofthe medicaments used. For example, a sustained action pill with 10layers of very soluble or hydroscopic medicaments such as ascorbic acid(vitamin C) separated by 9 control coatings, becoming permeablesequentially after exposure to intestinal fluids are formed as describedin Example I, will medicate the intestines as shown in Table 1.

aieaep'ro amphetamine sulfate, the following table applies to medicationin the alimentary canal:

When pills as described in connectionvwith. Example I incorporatemedicaments relatively insoluble in water, such as phenobarbitol, the.following table. applies:

Table 3 Time Pills Heat Medication Oven Temperature Treated Period,

in Oven, Hours Hours 6 9 to 10 4 8'to 9 2 6 to 7 From the foregoingtables, it will be apparent'that-the greater the solubility of themedicament,- the longer the pills must be heat treated to provide thesame release period, other factors being equal.

A further method of producing sufiicient pills to manufacture 500,000mg. dextroamphetamine sulfate tablets is set forth in the followingexample:

EXAMPLE II Step 1.To form pillets (center cores) place 100 lb. of'coarsegranulated sugar in a closed revolving coating pan of' about 40"diameter and rotate. Moistenthe sugar with one quart methyl alcoholcontaining 5% water, rotating the pan until all the solution is evenlydistributed throughout the granulated sugar, and then dust with adusting powder containing 50% sugar and 50% corn starch. Repeat thisprocedure three times drying the material between each moistening.Continue moistening with a solution made of one gallon of water(lukewarm) in which 5 lbs. of powdered sugar has been dissolved and thendust and dry after each moistening until. desired size pillets areobtained. A preferable size is approximately 13 to 16 mesh. Drythe-resulting pillets with a high temperature heating unit. Toremove allexcess large pillets screen them through a size screen that willeliminate those pillets in excess of about ,4 diameter. Coat the pilletswith 5 coatings of U.S.P. syrup (sugar and water syrup) and dry to givethem a smooth surface in preparation for a layer of medicament.

Step 2.Prepare a solution A-1 by mixing one gallon of water, one gallonof methyl or isoprophynol alcohol and 8 ounces edible soluble gelatin.Dissolve the gelatin into the water by placing it in a bath and heating.After the gelatin solution has been cooled to about 100 F. the alcoholis added and the solution mixed and strained to remove any solidifiedgelatin.

Step 3.Prepare several quarts of solution B-1 by mixing ethyl cellulose,shellac and methyl alcohol as follows: Provide an ethyl cellulosesolution inthe proportions of 25 gr. of ethyl cellulose in 100 cc.methyl alcohol, provide pharmaceutical glaze shellac (5 lb. shellac pergallon of methyl alcohol). To obtain 100 cc. of solution B-l mix '25 cc.of the ethyl cellulose solution, cc. of the shellac glaze and 50 cc.of'methyl alcohol:

Step 4.--To prepare the active ingredient-for coating;

after entry into the intestines.

10 pulverize 7.5 kilograms of dextroamphetamine sulfate to avery finemesh. powder and. mix in about 1% of talent magnesium stearate forlubrication purposes.

Step 5..-Place 32.5 kg. of the pillets formed in step 1 inan enclosedcoating pan of about 40 diameter and moisten with two pintsa solutionA-lwhilethe pilletsare being revolved until the solution is thoroughlycoated on the pills. Open the pan and blow hot airinto it forapproximately 10 seconds to dry the interior pan wall. Then add 2.5 kg.of the pulverized dextroamphetamine sulfate and revolve in the closed.pan until all. of the active ingredient adheres to the pills. Dry thepills with thehot air blower.

Step 6 .Rotate thedry pillets in the coating pan, spray on two pints ofwarm solution B-1 and dry the coating well. Then spray on two more pintsof solution B'-1 while the pills are rotating in the coating pan. Dustwith a small amount of talc if necessary between coatings to preventsticking.

Step 7.Repeat steps 5 and 6.

Step 8.-Repeat step 5 and dry well.

Step 9.-Weigh the pills and divide into three equal portions. Place oneportion aside and rotate the two re: maining' portions in the coatingpan and repeat the coating procedure of step 6 on these two portions 3times.

Step 10.--Remove half of the pills from the coating pan and repeat 3times coating step 6 on the pills remaining in the pan.

Step 11.-Place all three portions of the pills together in thecoating-pan and rotate for about 2 hours with the hot airblower turnedon. This rounds out the pills and mixes the three portions thoroughly.

Step 12.-Allow the pills to cool 12 hours.

Step 13.Place the pills in an oven and heat treatfor 10 hours at atemperature of from 97 to 98 F.

Step. 14.Assay the pills to determine the quantity of them in milligramsnecessary to incorporate in each tablet to release the selected quantityof drug. In the present example the assay results will show that about130 mg. of pills are required to release 15 mg. dextroamphetaminesulfate.

Step 15.To form tableting filler material mix 100 lbs. powdered sugarwith 1% magnesium stearate (for lubrication).and granulate with a'3%ethyl cellulose solution formed by mixing 3 grams of ethyl cellulosewith 100 cc. of chloroform.

Step 16.-Mix the pills with the tablet filler material in such amountsthat the maximum weight of the pills compressed into the tablets by atableting machine is about 50% of the weight of the tablets. Use 260 mg.of the pills-filler mixture in a tableting machine to form each of about500,000 15 mg. dextroamphetamine tablets incorporating the inventivesustained action pills.

The three portions of pills of Example II initiate release of medicamentat three different times. Thus, the first portion releases its outerlayer immediately followed by its second and third layers in the nexttwo hours. Since the outer layer of the second portions of pills iscovered with a thicker control membrane, release therefrom is initiatedabout 3 hours after it enters the intestines, and release from the thirdportion is initiated about 6 hours Since each of the three portionsprovides release of medicament over a three hour period, theirsequential action affords release over a nine hour period and medicationfor at least that long.

Any desired number of groups of the inventive sus: tained action pillsmay be incorporated in tablets or capsules (see Figure 4) to providerelease of medicament and medication over extendedperiods. The groupsforclassesof pillsmay be designed to release sequentially or, if desired,the release from two groups may overlap to insure continuityofmedication.

The following table indicates the manner of releaseofdextroamphetaminesulfate from a sample tablet produced in accordance with ExampleII.

Total material released over period of 9 hours, 14.93 mg.

. To contrast the release of medicament over long periods with therelease of dextroamphetamine sulfate in the gastro-intestinal tract froma conventional pill protected by an enteric coating of 50% shellac and50% ethyl cellulose, the following table should be examined:

Further exemplary tablets incorporating the inventive pills may beformed as follows:

EXAMPLE III Step 1.-Place 107 lbs. of pillets (center cores) formed inaccordance with step 1 of Example II in a 40 diameter coating pan.

Step 2.Moisten the pills in the coating pan with one pint of solutionA-l (see step 2 of Example 2). Rotate pan until all of the solution A-lis well distributed and the pan dry. Dust the pills with 6 lbs. 9 ouncesof a powder containing 10% nitroglycerin and 80% beta-lactose. Continueto rotate the coating pan until all the nitroglycerin is absorbed by thepillets and then turn on the warm air and dry well. Step 3.Spray thepillets with 2 pints of solution B-l (see step 3 of Example II), dry anddust with about 1 lb. of talcum powder. Then coat with 2 more pints ofsolution B-l, dry and dust with talc.

Step 4.--Repeat steps 2 and 3 nine times. Dry the pills well and coatwith 8 layers of shellac, one pint for each coat, dusting between eachlayer. The total weight of the pills will now be about 197 lbs.

Step 5 .-Heat treat the pills for 12 hours at a temperature of 97 to 98F.

Step 6.To provide tablet filler material, mix 100 lbs. powdered sugar, 1lb. talc or magnesium stearate for lubrication, and granulate with asolution of 3 gr. ethyl cellulose and 100 cc. of chloroform. Addnitroglycerin powder to the filler material to provide instantmedication in the stomach.

Step 7.-Dissolve 5 gr. of red coloring in 1 pint of water and 3 pints ofmethyl alcohol. Coat 4 layers of red coloring solution on the pills, onepint per coat.

Step 8.Assay the pills and filler material to determine the quantity ofpills and the weight of filler material necessary to provide 6.5 mg.nitroglycerin. In the prescnt'example the assay results will show thatabout 224 mg. of pills and 224 mg.of filler material will provide properamount of drug.

Step 9.-Supply the mixed pills and filler material to a tabletingmachine set for 448 mg. tablets. The matcrial specified in this examplewill besufiicient to manufacture about one million tablets incorporatingthe inventive sustained action pills.

The following table shows the amount of material released from 6.5 mg.nitroglycerin tablets produced in accordance with Example III.

Table 6 Drug Cumulative Exposure in Hours Released Drug in Mg. Releasedin Mg.

Gastric Fluid:

1 1. 04 1. 04 Intestinal Fluid:

Material released in 11 hours, 6.3 mg.

It is apparent from Table 6 that the inventive sustained action pillsprovide medication in the alimentary canal over an extended period andthe nitroglycerin released following the initial release of medicamentfrom the tablet filler is about the same during each hourly period.Although the alimentary canal absorbs nitroglycerin within a few minutesafter release, its therapeutic value in the body lasts over one hour sothat constant medication is provided by the inventive pill. If thetherapeutic efiect lasted for longer periods, it would not be necessaryto'provide as many layers of material as are found in this pill.

Heat treating the pills at temperatures of 97 to 98 F. has provensatisfactory since it softens the membrane material (ethyl cellulose,cellulose acetate phthalate, for example) and the pore closure substance(shellac, beeswax, polyethylene glycol, for example) to close graduallythe pores in the control membrane. The smaller pores resist penetrationby fluids for longer periods. Higher heat treating temperatures may beused for shorter periods to effect the same results as heat treating at97 F., bearing in mind, however, that excessive temperatures willdestroy certain medicaments. Moreover, such temperatures must not behigh enough to aifect adversely the pore closure substance and render itunsuitable to perform its function of closing the membrane pores andwithstanding alimentary fluids. The pills may be heat treated at lowertemperatures for longer periods to effect the same results as heattreating at 97 F. so long as the temperatures are high enough to softenthe membrane and pore closure substance.

Referring next to Figure 2, a tablet 22 containing a number of the pills10 is illustrated. The tablet 22 is basically pressed from a powderconsisting of starch and sugar in the ratio of starch to 10% sugar, forexample. The toughness of the pills 10, due to the ce lulose filterpreferably on its exterior in this instance, permits a firm tablet 22 tobe pressed without cracking the pills 10. Thus, one tablet may contain aplurality of the pills 10 for releasing medicament in the stomach andsubsequently in the intestines. Alternatively, the tablet 22 may containa plurality of pills adapted to release medicament in the stomach and afurther plurality of pills for releasing medicament in the intestines.Thus, the layers of medicament in the first-mentioned pills would beseparated by control coatings formed from cellulose acetate phthalateand the layers of medicament in the last-mentioned pills would beseparated by control coatings formed from ethyl cellulose.

For example, the tablet 22 may both stimulate the stomach causing it toempty into the intestines and subsequently act as a laxative in theintestines. This is 13 sometimes preferable to employing two difierentdrugs in a single pill since it protects against any possible illeffects from the reaction of the drugs with each other.

Turning to Figure 3, a pill 23 is pressed from a starch and sugar powdersimilar to that employed in forming the tablet 22, and contains aplurality of the pills 10. It may be formed and utilized in the samemanner as set fiorth in connection with the tablet 22.

Referring next to Figure 4, a capsule 24 is formed of two halves 25 and26 in a conventional capsulating machine, the half 26 being transparentas shown. A desired number of the pills are carried within the capsule24 to assist in oral administration of medicament. The material formingthe capsule may dissolve afterexposure to stomach fluids. At that timethe sustained action pills 10 contained therein will initiate release ofmedicament over any desired extendedperiod as discussed in detail above.The sustained action pills 10 found in the capsule 24 may be of severaldifferent types or classes, one type releasing drugs over a period ofthree hours, the second type initiating release of medicament afterthree hours for an additional three hours, etc.

It will be understood that the above-described embodiments of theinvention are illustrative only and modifications thereof will occur tothose skilled in the art. Therefore, the invention is not to be limitedto the specific embodiments disclosed herein but is to be defined by theappended clairns.

I claim:

1. In a'sustained action pill to release medicament over an extendedperiod for medication of the alimentary tract, a plurality of medicamentlayers, heat treated control membranes having pores containing a poreclosure substance separating adjacent medicament layers, alimentaryfluids rendering each of the membranes perineable after acting thereonfor a period by removing at least partially the pore closure substancefrom the pores of the membranes, the temperature and duration of themembrane heat treatment softening the membrane and pore closuresubstance to decrease the size of the membrane pores and lengthen theperiod the control membranes resist penetration by the alimentaryfluids, the alimentary fluids penetrating the permeable membrane toleach its corresponding medicament layer therethrough and thereafter wetthe next membrane to render it permeable after a period of exposurethereto, each of the membranes remaining permeable and intact to controlfluid flow at least until substantially all of the medicament in thelayer therebeneath has been leached therethrough.

2. A pill as defined in claim 1, wherein the membrane is formed of ethylcellulose and the pore closure substance is shellac, and the alimentaryfluids rendering the membranes permeable consist of intestinal fluids.

3. A pill as defined in claim 1, wherein the membrane is formed ofcellulose acetate phthalate and the pore closure substance is beeswaxand the alimentary fluids rendering the membranes permeable consist ofintestinal fluids.

4. A pill as defined in claim 1, wherein the membrane is formed of ethylcellulose and the pore closure substance is polyethylene glycol, and thealimentary fluids rendering the membranes permeable consist of stomachfluids.

5. A tablet incorporatingpills as defined in claim 1,

id in which a plurality of different groups of pills are provided, eachgroup consisting of pills releasing medicament over a different extendedperiod after exposure to alimentary fluids, thereby providing medicamentrelease and therapeutic effects over an extended period of time.

6. A tablet incorporating pills as defined in claim 1, in which some ofthe pills release medicament over a first extended period and other ofthe pills release medicament over a second different extended period notcoextensive with the first period, whereby medicament is released ovcr aperiod greater than either one of the first and second periods.

7. In a sustained action pill to release medicament over an extendedperiod for medication of the intestines, a plurality of medicamentlayers, heat treated control membranes comprising to ethyl cellulose and30 to 5% shellac separating adjacent medicament layers, intestinalfluids rendering each of the membranes permeable after acting thereonfor a period by removing at least partially the shellac from the ethylcellulose pores, the temperature and duration of the membrane heattreatment softening the ethyl cellulose and shellac to decrease the sizeof the ethyl cellulose pores and lengthen the period the controlmembranes resist penetration by the intestinal fluids, the intestinalfluids penetrating the permeable membrane to leach its correspondingmedicament layer therethrough and thereafter wet the next membrane torender it permeable after a period of exposure thereto, each of themembranes remaining permeable and intact to control fluid flow at leastuntil substantially all of the medicament in the layer therebeneath hasbeen leached therethrough.

8. In a method of producing sustained action pills releasing medicamentover extended periods, the steps of coating alternately on pillets aplurality of medicament layers and control membranes of ethyl celluloseand shellac, and heat treating the pills for a predetermined time and ata temperature sufficient to soften the ethyl cellulose and shellac todecrease the size of the ethyl cellulose pores to enable each of thecontrol membranes to withstand intestinal fluids for a selected timeinterval before beingrendered permeable by such fluids.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES JAPA, January 1934, p. 75. Silver et al.: Manuf. ofCompressed Tablets, F. J.

Stokes Machine Co., Philadelphia, Pa., 1944, pp. 22 and 23.

Drug and Cos. Ind., vol. 63, No. 4, October 1948, p. 431.

Drug and Cosmetic Ind., September 1948, p. 286.

UNITED STATES PATENT O-FFCICE CERTIFICATE OF CORRECTION Patent No, 2 928770 March 15,, 19cc Frank M, Bardani It is hereby certified that errorappears in the printed specification of the above numbered patentrequiring correction and that the said Letters Patent should readascorrected below.

Column 2 line 62 strike out "as"; column 9 line 63 for "it" read themcolumn 10 line 6,, for "in" read am of column l3 line 57 for intestinalread stomach line 62 for "stomach" read intestinal Signed and sealedthis. 23rd day of August 1960..

(SEAL) Attest:

KARL H. AXLINE ROBERT C. WATSON Attesting Officer Commissioner ofPatents

1. IN A SUSTAINED ACTION PILL TO RELEASE MEDICAMENT OVER AN EXTENDEDPERIOD FOR MEDICATION OF THE ALIMENTARY TRACT, A PLURALITY OF MEDICAMENTLAYERS, HEAT TREATED CONTROL MEMBRANES HAVING PORES CONTAINING A POERCLOSURE SUBSTANCE SEPARATING ADJACENT MEDICAMENT LAYERS, ALIMENTARYFLUIDS RENDERING EACH OF THE MEMBRANES PERMEABLE AFTER ACTING THEREONFOR A PERIOD BY REMOVING AT LEAST PARTIALLY THE PORE CLOSURE SUBSTANCEFROM THE PORES OF THE MEMBRANES, THE TEMPERATURE AND DURATION OF THEMEMBRANE HEAT TREATMENT SOFTENING THE MEMBRANE AND PORE CLOSURESUBSTANCE TO DECREASE THE SIZE OF THE MEMBRANE PORES AND LENGTHEN THEPERIOD THE CONTROL MEMBRANES RESIST PENETRATION BY THE ALIMENTARYFLUIDS, THE ALIMENTARY FLUIDS PENETRATING THE PREAMBLE MEMBRANE TO LEACHITS CORRESPONDING MEDICAMENT LAYER THERETHROUGH AND THEREAFTER WET THENEXT MEMBRANE TO RENDER IT PERMEABLE AFTER A PERIOD OF EXPOOSURETHERETO, EACH OF THE MEMBRANES REMAINING PERMEABLE AND INTACT TO CONTROLFLUID FLOW AT LEAST UNTIL SUBSTANTIALLY ALL OF THE MEDICAMENT IN THELAYER THEREBENEATH HAS BEEN LEACHED THERETHROUGH.